Schistosomiasis is a major neglected helminthic disease suffered by over 200 million people throughout the world. Critical to understanding schistosomiasis is the notion that it represents an immunologically mediated disease, that is, the damage to the affected tissues is largely inflicted by the host's own immune system. Morbidity and mortality are due to a pathogenic CD4 T lymphocyte-mediated immune response against parasite egg Ags. This results in granulomatous and fibrosing inflammation, which in the case of the species Schistosoma mansoni, takes place in the liver and intestines. The magnitude of disease varies greatly from individual to individual but in a minority of patients there is severe disease and death. S. mansoni infection in a mouse model similarly results in marked strain variation of immunopathology with severe pathology in CBA mice being mediated by proinflammatory IL-17- producing CD4 T cells (Th17 cells) specific for schistosome egg Ags. In contrast, pathology in C57BL/6 (BL/6) mice is mild and largely driven by Th2 cells. Our lab has shown that dendritic cells (DCs) from CBA mice differ sharply with those from BL/6 mice in that they vastly over-express the C-type lectin receptor (CLR) CD209a (SIGNR5), a homolog of human DC-SIGN. Since CLRs can sense glycans such as those produced by schistosome eggs, the proposed studies are driven by the hypothesis that high expression of CD209a on DCs plays a decisive role in mediating the development of severe immunopathology. Recent studies showing the loss of Th17 cell-stimulatory activity in CBA DCs following CD209a knock-down, vs. the gain of this function by CD209a-transfected BL/6 DCs, clearly support this hypothesis. The goal of this proposal is to elucidate the mechanisms by which CD209a induces pathogenic Th17 cells that orchestrate the development of severe hepatic inflammation in schistosomiasis. Aim 1 of the proposal is to broadly analyze the effect of CD209a on the pathogenic Th17 cell response to schistosome eggs in vivo and in vitro; aim 2 is to characterize the CD209a receptor-egg ligand interaction by identifying the schistosome egg-derived glycan motifs that engage CD209a, as well as the sites on CD209a involved in glycan recognition and downstream signal transduction; and aim 3 is to elucidate the CD209a- activated DC signaling pathways leading to proinflammatory IL-1? and IL-23 production and Th17 cell activation. The proposed experiments represent a focused approach to understanding the striking variation in morbidity and mortality in schistosomiasis. Our studies will dissect the pathogenic CD209a-initiated pathways and thus unravel mechanisms by which genetically endowed DCs sense parasite cues that result in Th17 cell-mediated severe disease. Examination of mice expressing transgenic human DC-SIGN will test its inherent pathogenicity in the mouse and thus provide a bridge to being evaluated in human severe vs. mild pathology. It is expected that these studies will uncover concrete targets for immunointervention, which should be amenable for consideration in the human patient population.